Safety and Immunogenicity of the mRNA-1273 Coronavirus Disease 2019 Vaccine in Solid Organ Transplant Recipients

Abstract

Background: Solid organ transplant recipients (SOTRs) are at high risk for severe COVID-19.

Methods: This open-label, phase 3b trial evaluated mRNA-1273 in 137 kidney and 77 liver SOTRs and 20 immunocompetent participants. In part A, SOTRs received three 100-µg doses of mRNA-1273; immunocompetent participants received 2 doses. In part B, an additional 100-µg dose was offered ≥4 months after the primary series. Here, we report interim trial results.

Results: mRNA-1273 was well-tolerated in SOTRs. Four serious adverse events were considered vaccine related by the investigator in 3 SOTRs with preexisting comorbidities. No vaccine-related biopsy-proven organ rejection events or deaths were reported. mRNA-1273 elicited modest neutralizing antibody responses after dose 2 and improved responses after dose 3 in SOTRs. Post-dose 3 responses among liver SOTRs were comparable to post-dose 2 responses in immunocompetent participants. Post-additional dose responses were increased in SOTRs, regardless of primary series vaccination. In liver SOTRs, post-additional dose responses were ∼3-fold higher versus post-dose 2 but lower than immunocompetent participant responses. Most kidney SOTRs received multiple immunosuppressants and had reduced antibody responses versus liver SOTRs.

Conclusions: mRNA-1273 was well-tolerated, and dose 3 and the additional dose improved antibody responses among SOTRs.

Clinical trials registration: NCT04860297.

Keywords: COVID-19; immunocompromised; mRNA-1273; solid organ transplant recipients; vaccine.

Graphical Abstract

Figure 1.

Participant enrollment and analysis populations. Enrollment of solid organ transplant recipients (SOTRs) and immunocompetent participants in part A took place between 16 April 2021 and 28 February 2022. SOTRs received a 3-dose primary series of mRNA-1273 or a third dose if previously vaccinated with 2 doses of mRNA-1273. Immunocompetent participants in part A received only 2 doses. SOTRs and immunocompetent participants from part A and SOTRs who previously completed primary vaccination outside of the study were enrolled in part B between 4 March and 23 August 2022 and received an additional dose. Participants with positive or missing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) status at baseline (part A) or pre-additional dose (part B) were excluded. Other reasons for exclusion were doses not received per schedule (ie, doses not received or received out of window) and missing data (ie, pre- or postbaseline data [part A] or pre- or post-additional dose data [part B]). *Safety was assessed in the safety set combined for part A and part B, comprising a total of 214 SOTRs and 20 immunocompetent participants. Abbreviation: PPIS, per-protocol immunogenicity set.

Figure 2.

Local (A) and systemic (B) adverse reactions (ARs) by severity and dose among all solid organ transplant recipients (SOTRs; solicited safety sets). The percentage of SOTRs who reported solicited local and systemic ARs within 7 days of receiving mRNA-1273 in parts A and B are shown, stratified by grade and dose. Data are representative of the solicited safety sets, comprising all participants who reported a solicited AR after receipt of dose 1, dose 2, dose 3, or the additional dose during the study. The numbers of participants who reported data for any solicited AR were as follows: after dose 1, n = 58; after dose 2, n = 60; after dose 3, n = 125; after the additional dose, n = 157.

Figure 3.

Neutralizing antibodies (nAbs) against ancestral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at baseline and after mRNA-1273 dose 2 and 3 (part A per-protocol immunogenicity set [PPIS]) and the additional dose (part B PPIS). nAbs were evaluated by means of pseudovirus neutralization assay at baseline (day 1 in part A; before additional dose in part B), 28 days (1 month) after dose 2 (PD 2) in part A, and 28 days (1 month) after the additional dose in part B in immunocompetent participants and solid organ transplant recipients (SOTRs). nAbs were also evaluated in part A 28 days (1 month) and 6 months after dose 3 (PD 3) in SOTRs; samples were not collected from immunocompetent participants at these time points because that they did not receive dose 3. Data are representative of the part A PPIS and the part B PPIS, comprising participants who tested negative for SARS-CoV-2 at the respective baseline, received vaccine doses according to schedule, and had no major protocol deviations. The numbers of participants with nonmissing data at the corresponding time points were as follows for part A: baseline, 40 SOTRs and 17 immunocompetent participants; 1 month after dose 2, 38 SOTRs and 17 immunocompetent participants; 1 month after dose 3, 81 SOTRs; and 6 months after dose 3, 31 SOTRs. The corresponding numbers for part B were as follows: baseline (pre-additional dose), 96 SOTRs and 3 immunocompetent participants; and 1 month after additional dose, 92 SOTRs and 3 immunocompetent participants. Data labels above each bar represent actual geometric mean concentrations (GMCs), and error bars represent 95% confidence intervals (CIs). Antibody values reported as below the lower limit of quantification (LLOQ) were replaced by 0.5 × LLOQ, and values above the upper limit of quantification (ULOQ) were replaced by the ULOQ.

Figure 4.

Neutralizing antibody (nAb) responses by immunosuppressive therapy (IST) regimen and dose among solid organ transplant recipients (SOTRs) (per-protocol immunogenicity set [PPIS]). nAbs were evaluated by means of pseudovirus neutralization assay at baseline (day 1 in part A; before additional dose in part B), and 28 days (1 month) after dose 2 (PD 2), 28 days (1 month) after dose 3 (PD 3), and 28 days (1 month) after the additional dose in SOTRs. Data are representative of the part A PPIS and part B PPIS, comprising participants who tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the respective baseline, received vaccine doses according to schedule, and had no major protocol deviations. The IST regimens at each time point were as follows for part A: baseline, mycophenolate mofetil (MMF) + tacrolimus (Tac) + prednisone (n = 15), MMF + Tac (n = 6), other combinations (n = 15), and Tac (n = 4); 1 month after dose 2, MMF + Tac + prednisone (n = 13), MMF + Tac (n = 6), other combinations (n = 15), and Tac (n = 4); and 1 month after dose 3, MMF + Tac + prednisone (n = 12), MMF + Tac (n = 6), other combinations (n = 14), and Tac (n = 3). The regimens for part B were as follows: baseline, MMF + Tac + prednisone (n = 33), MMF + Tac (n = 20), other combinations (n = 29), and Tac (n = 14); and 1 month after additional dose, MMF + Tac + prednisone (n = 32), MMF + Tac (n = 19), other combinations (n = 28), and Tac (n = 13). Data labels above each bar represent actual geometric mean concentrations (GMCs), and error bars represent 95% confidence intervals (CIs). Antibody values reported as below the lower limit of quantification (LLOQ) were replaced by 0.5 × LLOQ, and values above the upper limit of quantification (ULOQ) were replaced by the ULOQ. Other combinations included combinations of Tac, azathioprine, and prednisone; mycophenolate and prednisone; Tac and azathioprine; other rare combinations; and other rare single ISTs.